Nephrolithiasis occurs in approximately 1 in 10 individuals in the United States with increasing prevalence noted over the past three decades. Recurrence is common occurring in around 50% of these patients, many of whom require surgical intervention. An estimated 5-6 billion dollars a year is spent on the treatment of kidney stones. Symptoms of kidney stones include flank pain, blood in the urine, nausea and vomiting. Beyond acute attacks associated with considerable morbidity and cost, recent reports have identified associations between kidney stone formation and increased risk for the development of hypertension, chronic kidney disease, end stage renal disease and myocardial infarction. Therefore, nephrolithiasis not only impacts socioeconomics but also has broader public health implication. Genetic and environmental risk factors are both linked to nephrolithiasis with about 40% of patients presenting with kidney stones having at least one relative who is also a stone former. Genetic variants causative of monogenic forms of nephrolithiasis have been well defined. However the frequency of monogenic mutations and their presence as predisposing factors of disease is poorly understood within the idiopathic stone forming population. We have identified that heterozygous mutations of HOGA1, a gene associated with the onset of primary hyperoxularia Type III, are present within idiopathic stone formers and absent in matched controls. These findings suggest that the presence of these mutations could be indicative of increased risk for kidney stone formation within these patients. We therefore propose to; Aim 1: Validate and expand our previous studies to define that genetic variations of HOGA1 are a predisposing factor for idiopathic calcium-oxalate stone formation, and Aim 2: Mutational analysis of genes involved in kidney stone formation for determination of genetics of risk. These studies will identify the frequency of known genetic variants associated with monogenic forms of nephrolithiasis within idiopathic stone formers and associate their presence with heightened risk. Patient genomic DNA, blood, clinical data and risk data are available from the Mayo Clinic Kidney Stone Registry. Genomic DNA and RNA will be assessed for mutations within HOGA1 and their significance as predisposing factors for disease evaluated through statistical analysis and compared to environmental risk factors. Furthermore, genetic variants within AGXT, GRHPR, CLCN5, OCRL1, SLC3A1, SLC7A9, and APRT will be analyzed for frequency in idiopathic nephrolithiasis patients and control populations to determine their role as predictive genetic markers for idiopathic disease risk. This proposed study has the potential to identify genetic variants that are predisposing factors for idiopathic kidney stone formation and are predictive of disease risk. These studies have relevance to personalized treatment regimens for disease intervention, targeted prevention of reoccurrence and development of genetic tests for early diagnosis of patients at higher risk of idiopathic nephrolithiasis.